Targeted protein degradation is a powerful pharmacological strategy that harnesses the ubiquitin proteasome system to eliminate disease-relevant proteins, including otherwise undruggable proteins1. Here we report an unbiased and broadly applicable platform for the systematic discovery of molecular glues across diverse E3 ligases. Using multiplexed mass spectrometry-based chemical screening, we identified M12, a molecular glue that reprogrammes the E3 ligase DCAF11 to degrade DDX18. Mechanistically, M12 functions as a prodrug that is activated through glutathione S-transferase-mediated glutathionylation. The glutathione moiety binds to an evolutionary conserved glutathione-binding site on DCAF11, and the exposed M12 moiety facilitates neo-substrate recruitment. We demonstrate that this glutathione-dependent mechanism readily enables targeted degradation of a range of proteins. Collectively, these findings establish that metabolically activated compounds can redirect E3 ligase function, thereby expanding the scope of targeted protein degradation and chemically induced proximity.

Understanding how adverse life events trigger stress-related behavioural changes remains an unresolved challenge. The amygdala is integral to emotion and stress responses1 and comprises astrocytes, neurons and other cells. Here we show that amygdala astrocytes contribute to stress-related behaviours through signalling mechanisms related to their primary cilia2. Amygdala astrocytes are altered during stress at the protein and gene expression level, display reduced expression of molecules related to primary cilia3,4 and have morphologically short primary cilia5,6. G protein-coupled receptors (GPCRs) are central to astrocyte7 and primary cilia2,8,9 function. Therefore, we speculated that GPCR signalling activation might be beneficial in stress-related behavioural disorders. We identified amygdala astrocyte GPCRs as regulators of responses following stress. Chemogenetics and targeting of native sphingosine-1-phosphate receptor 1 (S1PR1) GPCRs led to the restoration of astrocyte primary cilia length, corrected molecular alterations and improved stress-related behaviours. Cilium-related genes were abundantly expressed in human amygdala astrocytes, with many displaying disrupted expression in stress-related brain disorders. S1PR1 was also highly expressed in amygdala astrocytes from human tissue. Selective genetic disruption of amygdala astrocyte primary cilia in mice altered some stress-related behaviours and gene expression of astrocytes and parenchymal cells. These data confirm that astrocytic cilia have important roles in this brain nucleus. In summary, amygdala astrocytes and their primary cilia are disrupted during stress, and their restoration is accompanied by stress-related molecular and behavioural improvements. Astrocyte primary cilia-related mechanisms may therefore provide new treatment strategies for stress-related and other brain disorders.

Structural anisotropy is ubiquitous in nature and governs orientation-dependent properties and functions1,2. Recreating biomimetic anisotropy in hydrogels-water-rich soft materials widely used in biomedicine-has proven challenging3. Here we report a phenomenon termed shear-extensional in situ particle-to-fibre transformation (SHIFT) and demonstrate the SHIFT printing of highly aligned hydrogel microfibres (5-30 μm in diameter). In SHIFT, particle-embedded hydrogel is extruded in a controlled manner, in which the discrete particles and surrounding matrix experience opposite phase transitions, concurrently transforming particles into well-aligned subvoxel microfibres. SHIFT establishes a methodology for creating anisotropy from droplets, which is dominated by extensional flow of sol-gel two-phase systems. It constitutes a versatile upstream manufacturing approach that can be readily adapted into three-dimensional printing and microfibre spinning scenarios in a highly accessible manner. The pronounced structural anisotropy enables the formation of exceptionally long myotubes in vitro and accelerates regeneration in volumetric muscle loss. By implementing an in situ subvoxel manufacturing process within flow, SHIFT expands the ability to process soft materials.

Two-dimensional (2D) superconductors are emerging platforms supporting both strongly correlated physics and quantum information science1,2. Their reduced dimensionality, atomically flat interfaces and high crystallinity are particularly attractive for realizing compact lumped-element devices in superconducting circuits3-5. However, large-scale synthesis of monolayer 2D superconductors remains challenging as they are easily oxidized in air6. Here we report an 'encapsulation epitaxy' mechanism that enables the growth of large-area (more than 1 inch), air-stable, monolayer niobium diselenide (NbSe2) films (1L-NbSe2) and explore their potential for superconducting quantum circuits. This work represents a distinct growth phenomenon in which a 2D encapsulation layer, such as graphene or hexagonal boron nitride, pre-deposited on a 3D substrate (for example, SiO2 or Si3N4) simultaneously serves as a template for the epitaxial growth of 1L-NbSe2 underneath it at the encapsulation-substrate interface and as a protective capping layer against ambient degradation. The as-grown 1L-graphene/NbSe2 heterostructures exhibit robust superconductivity (superconducting transition temperature Tc ≈ 1 K) and enhanced charge density waves (CDWs; CDW transition temperature TCDW ≈ 177 K). We further demonstrate the integration of 1L-NbSe2 into superconducting circuits by developing oxidation-free transfer and superconducting edge-contact techniques. The 1L-NbSe2 in these circuits feature a measured kinetic inductance LK ≈ 0.7 nH □-1, making it suitable for quantum circuits requiring elements with high kinetic inductance. This encapsulation-epitaxy methodology enables the production of air-stable 2D superconductors and van der Waals heterostructures, holding promise for wafer-scale, monolithic fabrication of superconducting quantum circuitry.

Astrocytes contribute to the pathology of multiple neurological disorders, including the T cell-driven autoimmune disease of the central nervous system (CNS) multiple sclerosis and its mouse model, experimental autoimmune encephalomyelitis1. However, little is known about functional interactions between astrocytes and CD4+ T cells. Here using rabies barcode interaction detection followed by sequencing2, in combination with single-cell RNA sequencing, in vitro co-culture systems and cell-specific in vivo CRISPR-Cas9-based genetic perturbation studies, we established that astrocytes expressing CD40 and MHC-II promote CNS T cell autoimmunity. We harnessed universal labelling immune partnerships by SorTagging intercellular contacts3 to analyse astrocyte-interacting CD4+ T cells, finding that direct astrocyte-CD4+ T cell interactions enhance pathogenic T helper 17 cell responses in experimental autoimmune encephalomyelitis. In addition, we studied the effect of these interactions on astrocytes. Using in vivo subproteomic approaches4 and AlphaFold-Multimer predictions5, we established that CD40 activation in astrocytes by CD40L expressed by CD4+ T cells induces the accumulation of PLIN4-positive lipid droplets, which provide acetyl-CoA to promote p65 acetylation-dependent NF-κB activation and antigen presentation. Finally, we detected CD40+MHC-II+LD+ astrocytes in multiple sclerosis samples by single-nucleus RNA sequencing and immunohistochemistry. In summary, these studies define a previously unrecognized mechanism by which astrocytes promote CNS autoimmunity.

Variations of meiosis, which normally halve genetic complements prior to fertilization, can have profound consequences. For example, whole-genome duplications (polyploidy) have shaped the evolution and diversification of most angiosperm lineages. The century-long success of sugarcane interspecific hybrids has been attributed to unusual female restitution-an unreduced maternal gamete fusing with a normal haploid paternal gamete1,2. Here we generated haplotype-resolved genomes of octoploid Saccharum officinarum LA Purple and decaploid Saccharum spontaneum US56-14-4. Eight F1 hybrids between these species exhibited 2:1 maternal to paternal genomic ratios, with 2 assemblies revealing canonical haploid sets of approximately 40 paternal and approximately 80 maternal chromosomes. The maternal chromosomes comprise 40 pairs of duplicated, partially recombined sister chromatids that retain around 62.5% of maternal genetic diversity, characteristic of second division restitution. Using single-molecule long-read sequencing and a novel algorithm that is broadly applicable to polyploid genomes, we identified two classes of recombination breakpoints, including a previously unrecognized configuration supported by both recombinant and non-recombinant reads, across all hybrids and diagnostic of second division restitution. These findings resolve a century-old cytological debate, add new insights into meiotic variations, and offer a genomic approach to accelerate genetic gain in this globally critical sugar and bioenergy crop.

Magnetars are isolated neutron stars with exceptionally strong surface fields exceeding 1014 G (ref. 1). Their bright X-ray emission probes physical regimes in which quantum electrodynamics (QED) influences radiation propagation2-4. Strong magnetic fields induce polarization-dependent refractive indices in the vacuum5,6; such vacuum birefringence remains a long-standing but unconfirmed prediction of QED. Here we report phase- and energy-resolved polarization measurements of the radio-emitting magnetar 1E 1547.0-5408 obtained by coordinating X-ray and radio observations from the Imaging X-ray Polarimetry Explorer, the Neutron Star Interior Composition Explorer and the Parkes/Murriyang Observatory. We detect large polarization degrees (PDs) in the thermally dominant soft X-ray band, reaching phase-averaged values of 65% at 2 keV before substantially decreasing between 2 keV and 4 keV. At certain rotational phases, the 2-3 keV PD rises to nearly 80% while remaining high (≳40%) throughout the radio beam crossing. The phase-dependent X-ray and radio polarization angles are both consistent with the rotating vector model, suggesting that the emission geometries track the large-scale magnetic field of the star. Collectively, these characteristics challenge standard surface emission models using non-refractive propagation of light to infinity. Vacuum-birefringence-governed magnetospheric propagation can naturally explain the X-ray polarization signals. Our results represent a marked advance in probing this hallmark prediction of QED, opening a new cosmic window into superstrong-field quantum physics, thereby motivating further observational and theoretical studies concentrating on this domain.

Understanding doped Mott insulators is a fundamental goal in condensed matter physics, relevant to cuprate superconductors and other quantum materials1-3. The Hubbard model minimally describes such systems and has explicated some of their complex behaviour4,5. However, many open questions remain concerning the anomalous metallic states that emerge at low temperatures and intermediate doping and which, in cuprates, give rise to high-temperature superconductivity on cooling2,6,7. Here we observe a crossover between a normal metal and a pseudogapped metal in the Hubbard model using thermodynamic and spectroscopic measurements in a cold-atom quantum simulator, leveraging a recent several-fold reduction in achievable temperatures8. On cooling, the compressibility develops a maximum at intermediate doping, signalling an inflection point in the equation of state. We track this maximum versus interaction strength, revealing a line of thermodynamic anomalies in the phase diagram separating an underdoped from an overdoped metal at large interactions. Lattice modulation spectra in the underdoped regime show a loss of low-energy response, especially pronounced in the antinodal regions of the Brillouin zone, indicating a pseudogap. We use this signal to construct a pseudogap phase diagram versus interactions and doping. Our results experimentally establish and characterize the pseudogap metal in the Hubbard model, and suggest connections to charge order that can be studied in future work. Furthermore, this work demonstrates the utility of quantum simulation in addressing frontier problems in correlated electron physics.

Beneficial and maladaptive opioid effects are difficult to dissociate1-3, partly because dopamine signalling contributes to both these effect types4-13. Here we show that associative opioid-reward learning can be blocked even under conditions that elevate dopamine in the nucleus accumbens. We developed naloxoneDART, a cell-type-specific analogue of the clinical opioid receptor antagonist naloxone14,15, and delivered it to genetically defined accumbal cholinergic interneurons, selectively rendering these cells morphine-insensitive. Acquisition of morphine conditioned place preference was abolished in a target-engagement-dependent manner, without evidence of contextual or locomotor impairment: saline habituation was enhanced between sessions and unchanged within sessions, whereas morphine-evoked hyperlocomotion, sensitization and acute analgesia remained intact. Microdialysis revealed that cholinergic interneuron-specific naloxoneDART prevented morphine-induced acetylcholine reductions without detectably altering dopamine increases in the accumbens. These findings identify a cholinergic gate for associative opioid-reward learning, support an emerging dopamine-acetylcholine plasticity theory16,17, and motivate exploration of opioid-cholinergic strategies that may preserve acute analgesia while limiting early associative reward learning18-25.

Cancer cell lines remain foundational for research and drug discovery, yet they incompletely capture tumour diversity, lack linked patient context, and have undergone adaptation to culture. Tumour organoids are three-dimensional cultures derived from patient tissue that offer a powerful complement to cell lines1. Here we derived and characterized 256 clinically annotated tumour organoids directly from colorectal, oesophageal, ovarian, pancreatic and gastric cancers as renewable, genetically stable models. Extensive characterization of each model and matched patient tumour samples included whole-genome and transcriptome sequencing, and genome-wide CRISPR-Cas9 screens across 162 organoids mapped gene dependencies. Integrative analyses revealed genomic and clinical markers of dependency across common and rare subtypes, identified organoid-specific essential genes, and revealed targetable vulnerabilities following tumour evolution in paired pre- and post-treatment samples. In colorectal cancer, functional and pharmacological interrogation of the EGFR-RAS-MAPK axis uncovered differential effects of KRAS variant alleles. This open, publicly available resource provides a systematic map of gene dependencies in patient-derived organoids, expanding the model diversity and mechanistic insight needed to advance precision oncology.

The interaction between the magnetic field and turbulent convection in the Sun's photosphere drives the dynamics, evolution and structuring of its magnetized atmosphere. This interaction often takes place at or below the spatial resolution of modern-day observations. Here we report on high-spatial-resolution observations of the solar photosphere acquired using the world's first 4-m class solar telescope, the US National Science Foundation's Daniel K. Inouye Solar Telescope. Time sequence images reveal a far more complex and dynamic solar scene than previously observed. We identify ubiquitous magnetized Kelvin-Helmholtz instabilities at the edges of magnetic flux concentrations and provide experimental confirmation of a long-standing theoretical prediction1,2. The discovery of small-scale magnetized Kelvin-Helmholtz instabilities in the solar photosphere, which can be reproduced by high-resolution numerical simulations, has far-reaching implications for our understanding of the creation and dissipation of magnetic fields exhibiting vortex motion, which can lead to flux braiding. Our results support the picture of disjoint magnetic field concentrations in layers below the visible solar surface that connect to monolithic flux regions visible as facular concentrations and pores in the solar photosphere. Kelvin-Helmholtz instabilities are an efficient mechanism for transporting mass, energy, momentum and magnetic flux in magnetohydrodynamic systems, and they offer transformative insights into processes in magnetically active regions such as the one observed here.

A rational design for facilitating innovative cell death modes can substantially aid advances in antitumour therapy1,2. Here we design and implement a unique mode of immunogenic membranolytic cell death (mLCD) in tumour cells, characterized by time-lagged rupture from the lysosomal to plasma membranes; this approach was found to robustly potentiate immune checkpoint blockade therapy. This mode of mLCD was induced by the synthetic-acid-responsive membranolytic peptide (aMP) aMPC16-CA50, which exhibits hierarchical responsiveness to the decreasing pH associated with the tumour extracellular environment and lysosomes. aMPC16-CA50 activated an inflammatory transcriptional program in tumour cells, potentiating their ability to induce antigen presentation on class I major histocompatibility complex molecules on dendritic cells and the subsequent activation of T cells. The pH-responsive kinetics and membranolytic activity of the membranolytic peptides had a critical role in enhancing the immunogenicity of lytic tumour cells through the spatiotemporal regulation of the membrane-rupture processes. Furthermore, aMPC16-CA50 exhibited a considerable advantage in enhancing the antitumour efficacy of immune checkpoint blockade therapy through the promotion of antitumour immune response. Moreover, its systemic administration was well tolerated in mice. Overall, we successfully programmed a unique mode of immunogenic mLCD in tumour cells through the spatiotemporal regulation of membrane-rupture processes using a synthetic pH-responsive membranolytic peptide amenable to manipulation.

Altered energy metabolism is a shared driver across cardiometabolic diseases-the leading cause of death globally1. Energy metabolism varies between individuals and is partly heritable2-9. Here, to investigate the genetic basis of energy metabolism, we perform an exome-sequencing analysis of 1,032,116 people from America, Europe and Asia, and estimate associations between rare protein-coding variants and the ratio of triglyceride to high-density-lipoprotein cholesterol (TG:HDL)-an energy-state biomarker that we associate with diverse cardiometabolic risk factors and diseases. We identify 59 independent genes (P < 1.04 × 10-7) that are enriched for liver- and adipose-expressed master regulators of energy balance, storage and metabolism; 23 (39%) of these genes encode approved or clinical-stage drug targets. Ultra-rare protein-truncating variants in FNIP1 (allele frequency, 0.01%), which encodes a suppressor of energy expenditure and mitochondrial metabolism, are associated with a lower TG:HDL ratio, lower liver fat, lower glycaemia, favourable fat distribution and around 60% lower odds of cardiometabolic disease. FNIP1 knockdown in primary human hepatocytes induces lipid breakdown and lysosomal gene expression, while combined hepatic knockdown of Fnip1 with its paralogue Fnip2 or knockdown of its interactor Flcn protect against weight gain, reduce liver fat and enhance insulin sensitivity in mice fed a high-fat diet. Our study implicates the FNIP1 pathway in human energy metabolism and highlights its inhibition as a potential therapeutic strategy in cardiometabolic disease.

The development of new therapeutics and the validation of pathogenetic cancer mechanisms require representative laboratory models1,2. However, existing collections represent only a fraction of the diversity observed in human cancer2-4. Recent technologies have enabled efficient in vitro model derivation (for example, tumour organoids)5. However, whether these maintain essential properties of patient tumours during long-term expansion has not been systematically investigated. Here we present results of a large-scale international programme-the Human Cancer Models Initiative-which involved the generation of a resource of 665 next-generation models from 2,780 donors with 25 cancer types and integrated tumour-model whole genome, exome, methylome and transcriptome analyses. The resource provides 522 models with comprehensive clinical data, 153 models of rare cancers and 71 models from participants with non-European ancestry. Analyses of 421 matched tumour-model pairs reveal high genetic (97.8%) and epigenetic (95%) concordance and define correlates of model discordance. Single-nucleus RNA sequencing of tumour-model pairs reveals subsets of models in which culture conditions significantly influence cell states. Finally, we characterize model preservation of extrachromosomal DNA and post-treatment mutational signatures to provide opportunities to study therapeutic resistance. This model repository is being made available to the community-including multimodal molecular profiling, clinical information and integrative software tools-thus providing a valuable resource for preclinical investigation of cancer pathogenesis and treatment response.

Despite advances in precision oncology, effective personalized treatments are still lacking for most patients with cancer1. The Cancer Dependency Map (DepMap) accelerates this field by systematically identifying cancer vulnerabilities in diverse preclinical models. Data from over 1,300 cell lines have led to the discovery of new therapeutic strategies across multiple tumour types2. However, mapping cancer vulnerabilities using traditional cell lines has limitations, including insufficient cancer subtype representation and the impact of culture conditions on perturbation responses. Here we perform 147 genome-scale CRISPR screens and multi-omic characterizations of next-generation (NextGen) cancer models (organoids and spheroids) across 10 cancer types. This strategy enables the expansion of DepMap to cover new genomic and molecular subtypes and to identify new biomarker-associated vulnerabilities. These new models also preserve transcriptional programs that are silenced in traditional cell lines and facilitate the discovery of specific gene dependencies associated with these programs. Comparisons of traditional and NextGen cancer models enable further identification of distinct effects of growth format and culture medium on gene essentiality. The integrated dataset combines data from both model types to offer a valuable, expansive resource for exploring cancer vulnerabilities and is accessible via the DepMap portal.

Reshaping cortical circuits through stimulation represents an emerging therapy for the restoration of cognitive function1-5, yet the biological mechanisms that underlie its effects remain largely unexplored in humans. Here, to directly investigate the mechanisms of neuromodulation elicited by human brain stimulation, we developed an ex vivo platform that integrates microelectrode array stimulation with simultaneous recording and single-nucleus genomics from resected temporal cortex obtained from patients undergoing neurosurgery. We found that stimulation strengthens cell assemblies and then linked this effect to cell-type-specific gene regulatory networks. We further demonstrated the generalizability of these findings by identifying common cell-type-specific gene expression signatures in the human cortex following in vivo stimulation. Together, our results establish a foundation for identifying targetable genetic signatures linked with physiology that may be harnessed for therapeutic benefit via neuromodulation strategies.

Chronic viral infections are ubiquitous in humans, with individuals carrying multiple viruses that can reactivate during physiological stress, including severe illness1. Notably, SARS-CoV-2 infection has been shown to reactivate chronic viruses such as Epstein-Barr virus and cytomegalovirus, yet the full extent, temporal dynamics and immunological impact of viral reactivation in COVID-19 remain incompletely understood2-7. Here, leveraging multi-omic longitudinal data from 1,154 hospitalized patients with COVID-19 from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study, we reveal significant reactivation of Herpesviridae and Anelloviridae during acute COVID-19, with distinct temporal dynamics for different viruses, and demonstrate that reactivation correlates with disease severity, host immune effects and clinical outcomes. Although our results do not establish causation between virus reactivation and clinical outcomes, we highlight the prevalence of chronic viral reactivation during acute COVID-19 and long COVID. Our findings challenge the prevailing view that chronic viral reactivation is primarily a consequence of immunosuppression, demonstrating that reactivations occur frequently in immunocompetent individuals during severe illness and in association with increased systemic inflammation. Additionally, we demonstrate persistence of viral reactivation in convalescence, and report an association of Anelloviridae with long COVID. This study provides immune, transcriptomic and metabolomic signatures of viral reactivation that could inform future strategies to prognosticate and treat acute COVID-19 and long COVID.